MATERNAL SEPARATION--A MODEL OF OPIOID VULNERABILITY

母亲分离——阿片类药物脆弱性的一个模型

基本信息

批准号：
2898197
负责人：
STEPHEN G HOLTZMAN
金额：
$ 13.4万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-09-18 至 2002-08-31
项目状态：
已结题

项目摘要

DESCRIPTION: (Applicant's Abstract) Results of recent studies on rats indicate a relationship among responsiveness to stress, activity of the mesolimbic dopamine system, behavioral and neurochemical responses to psychomotor stimulant and opioid drugs, and drug-seeking behaviors. Male rats separated from their mothers for 180 min/day (MS180), but not 15 min/day (MS15), on postnatal days 2-14 have an enduring increased responsiveness of their hypothalamic-pituitary-adrenal axis to a variety of stressors. In preliminary experiments, adult MS180 rats had higher locomotor activity than did MS15 rats upon initial exposure to a novel environment; they also were more sensitive to the motor-stimulating effects of morphine upon both acute and repeated administration and had a larger dopamine response in the nucleus accumbens to an IV dose of cocaine. The purpose of this exploratory/developmental project is to determine if early maternal separation results in altered responsiveness to opioid drugs in adulthood, and therefore might provide an animal model for studying factors that contribute to vulnerability to drugs of abuse. Three interrelated hypotheses will be addressed in a circumscribed series of systematic experiments in which a limited number of prototype opioid or psychomotor stimulant drugs will be tested over a range of doses in well-established procedures in animal facility reared, MS15, and MS180 rats: tests of antinociception (analgesia), motor activity, and suppression of drinking. Using morphine, the plasticity of endogenous opioid systems will be assessed in tests of tolerance and naloxone-induced sensitization to its analgesic effects, physical dependence, and sensitization to its motor-stimulating effects. Opioid modulation of effects of drugs that act via brain dopamine systems will examined in tests of cross-sensitization to motor-stimulating effects of amphetamine and cocaine and the interaction of naloxone with those drugs. Results confirming the potential value of this animal model would form the basis for a more comprehensive study of pharmacological, behavioral, and neurochemical variables contributing to vulnerability to opioids and other abused drugs.

描述：（申请人摘要）最近对大鼠的研究结果表明，对压力的反应，中脑边缘多巴胺系统的活动，对精神运动兴奋剂和阿片类药物的行为和神经化学反应毒品和寻求毒品的行为。雄性老鼠与母亲分离产后第 2-14 天每天 180 分钟 (MS180)，但不是每天 15 分钟 (MS15) 他们的反应能力持续增强下丘脑-垂体-肾上腺轴对各种应激源的影响。在初步实验显示，成年 MS180 大鼠的运动活性高于 MS15 大鼠首次暴露于新环境时是否如此？他们也是对吗啡的运动刺激作用更敏感重复给药并产生更大的多巴胺反应伏核接受静脉注射可卡因。这样做的目的探索/发展项目是为了确定早期孕产妇是否分离导致成年后对阿片类药物的反应改变，因此可能提供一个动物模型来研究影响因素助长了滥用药物的脆弱性。三者相互关联假设将在一系列有限的系统性研究中得到解决实验中使用有限数量的原型阿片类药物或精神运动药物兴奋剂药物将在公认的剂量范围内进行测试动物设施饲养的 MS15 和 MS180 大鼠的程序：测试抗伤害（镇痛）、运动活动和抑制饮酒。使用吗啡，将评估内源性阿片类药物系统的可塑性在耐受性和纳洛酮诱导的镇痛敏化测试中效应、身体依赖性和对其运动刺激的敏感性影响。阿片类药物对通过大脑多巴胺起作用的药物的作用的调节系统将在运动刺激交叉敏化测试中进行检查安非他明和可卡因的作用以及纳洛酮与那些药物。结果证实了该动物模型的潜在价值将为更全面的药理学研究奠定基础，导致脆弱性的行为和神经化学变量阿片类药物和其他滥用药物。